CLINICAL RESEARCH
European Heart Journal (2014) 35, 1327–1334 doi:10.1093/eurheartj/ehu017
Arrhythmia/electrophysiology
Optimal rhythm-control strategy for recurrent atrial tachycardia after catheter ablation of persistent atrial fibrillation: a randomized clinical trial Xiao-Dong Zhang, Jun Gu, Wei-Feng Jiang, Liang Zhao, Li Zhou, Yuan-Long Wang, Yu-Gang Liu, and Xu Liu* Received 16 June 2013; revised 17 November 2013; accepted 29 December 2013; online publish-ahead-of-print 3 February 2014
Aim
Although catheter ablation (CA) has replaced antiarrhythmic drugs (AAD) as first-line treatment in selected patients with atrial fibrillation (AF), optimal treatment of recurrent atrial tachycardia (AT) after AF ablation remains unclear. This parallel randomized controlled study compared CA vs. AAD for recurrent AT after persistent AF ablation. ..................................................................................................................................................................................... Methods Two-hundred and one patients (aged 59.1 + 10.9 years, 68.7% male) with recurrent AT after persistent AF ablation were and results enrolled and randomized to either CA (n ¼ 101) or AAD (n ¼ 100) treatment. Primary endpoint was freedom from recurrent atrial tachyarrhythmia (ATa, including AT and AF) at 24-month follow-up. Composite secondary endpoints comprised procedural complications, long-term morbidity and improvement in quality of life (QoL). On an intention-to-treat basis, the CA group had a higher rate of freedom from recurrent ATa (56.4 vs. 34.0%; P ¼ 0.001). Adjusted Cox regression analysis showed a significant treatment effect with a hazard ratio of 0.538 (95% CI: 0.355 –0.816) in favour of CA. There was a higher proportion of periprocedural complications in the CA group (7.9 vs. 0; P ¼ 0.012), and of long-term adverse events in the AAD group (10.9 vs. 24.0%; P ¼ 0.014). Quality of life was significantly higher for CA. ..................................................................................................................................................................................... Conclusions This study demonstrates superiority of CA over AAD for recurrent AT after persistent AF ablation with regard to SR maintenance, long-term safety and QoL improvement. However, CA use might be limited by a higher risk for periprocedural complications.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Atrial fibrillation † Antiarrhythmic drugs † Catheter ablation † Atrial tachycardia † Recurrence † Quality of life
Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia.1 Although mainstay treatment for AF was pharmacological,2 catheter ablation (CA) has emerged as a very promising treatment in the last decade.3 – 6 Many randomized multicentre studies demonstrated the superiority of CA with regard to maintenance of sinus rhythm (SR) and improvement in symptoms, exercise capacity, and quality of life (QoL).3 – 7 However, recurrent atrial tachycardia (AT) after CA of AF is a rapidly growing clinical problem; it undermines the efficacy of CA8,9 because secondary ATs are
often incessant and poorly tolerated by patients. Selecting an appropriate rhythm-control strategy for recurrent AT is paramount to long-term SR maintenance. Catheter ablation and antiarrhythmic drugs (AADs) are the most commonly employed rhythmcontrol strategies. To the best of our knowledge, no study has substantiated preference for re-ablation as the first-line therapy for patients with recurrent AT after ablation. Moreover, the efficacy of treatment for AT and AF is usually not reported separately. We performed a prospective, randomized controlled study to investigate the optimal rhythm-control approach for recurrent AT after CA of persistent AF.
* Corresponding author. Tel: +86 2162821990 2603, Fax: 186 21628 21105, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected]
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Department of Cardiology, Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University, 241 West Huaihai Road, Shanghai 200030, China
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Methods Study population Two-hundred and one patients with recurrent persistent AT out of 986 consecutive patients who had undergone CA of persistent AF at Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University were prospectively enrolled. Inclusion criteria were patients with recurrent persistent AT, who had undergone persistent AF ablation at least 3 months before enrolment, and aged 18 or over. Patients were excluded if they had left atrial thrombus on transoesophageal echocardiography, contraindications to oral anticoagulant therapy (OAT), or any condition with life expectancy ,3 years.
Study design
After the blanking period, any over-30-s episode of atrial tachyarrhythmia (ATa) (including AF and AT) documented electrocardiographically or reported by the patient was considered a recurrence, after which a redo procedure or crossover to the alternative therapy could be performed. Atrial tachyarrhythmia was evaluated at 24 months after treatment. Study design and flow are presented in Figure 1.
Electrophysiological study and ablation procedure All 986 persistent AF patients followed a step-wise ablation strategy, including circumferential pulmonary vein (PV) isolation, complex fractionated atrial electrograms, and linear ablation. The methods and endpoints of ablation were described in detail in our previous study.10 For the enrolled patients, warfarin was discontinued and lowmolecular-weight heparin was used 3 days before ablation. All AADs were discontinued five half-lives before ablation. Unfractionated heparin (80 U/kg) was given after the first trans-septal puncture, and thereafter at 1000 U/h to maintain an activated clotting time between 300 and 350 s. Catheter ablation was performed with the guidance of an electroanatomical mapping system (CARTO, Biosense Webster, CA, USA). Atrial tachycardias could be classified as PV-driven, focal origin, macrore-entry/microre-entry, and unidentified. The approach for AT treatment entailed the following three successive steps: (i) PV origin to the tachycardia is ruled out; (ii) assessment is made for macrore-entrant circuits; and finally, if the mechanism remains undetermined, (iii) conventional mapping for a focal origin (either focal point or
Figure 1 Study design flowchart based on CONSORT guidelines. AAD, antiarrhythmic drug; CA, catheter ablation.
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This was an open, parallel-group, randomized trial. The study complied with the Declaration of Helsinki, and the protocol was approved by the local ethics committee. Eligible patients were assigned to one of the two study arms (CA or AADs) according to the randomization sequence generated by a random number table. All the patients were informed of the investigation and nature of the procedure; informed consents were obtained from all subjects. This study was designed to compare two different rhythm-control strategies in patients with recurrent AT after CA in terms of efficacy, complications and QoL. The first 3 months after procedure [CA/ electrical cardioversion (ECV)] were considered as a ‘blanking period’, during which repeat ablation and ECV should not be used.
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localized re-entry AT) is carried out. Accordingly, ablation strategy for AT included performing PV isolation, linear lesions, or ablating the ‘focus’ as necessary.11 Radio frequency power output was up to 40 W, 43??with 30 –40 s duration for each lesion and saline infusion rate of 20– 25 mL/ min. If the AT was not terminated, 300360 J DC cardioversion was applied to restore SR. After AT termination, patients usually were kept under surveillance for 20 – 30 min, and then PVI and bidirectional block of lines were evaluated and consolidated as required. Re-induction by rapid pacing after termination was at physician’s discretion.
Antiarrhythmic drugs
Blanking period management Antiarrhythmic drug was administered on a routine basis in both arms during the blanking period. As first-choice AAD, amiodarone was given orally at an initial loading dose of 600 mg/day for the first week and 400 mg/day for the following week, and thereafter at a daily maintenance dose of 200 mg/day. Rate control therapy, achieved with the administration of a beta-blocker and a non-dihydropyridine calcium-channel blocker, was used in patients with poorly tolerated AT. Oral anticoagulant therapy was restarted or continued if there was any episode of ATa.
Follow-up Follow-up visits were at 1, 3, 6, 9 months after treatment and every 6 months thereafter. All the participants were scheduled for outpatient clinic, when electrocardiogram (ECG) or 24-h Holter was obtained. Patients were always instructed to obtain an ECG when they had symptoms suggestive of ATa onset. Spiral computed tomography was performed at 3 months after ablation to assess for PV stenosis. Follow-up information was collected from our clinical database and questionnaire administered by telephone.
Quality of life assessment The Medical Outcomes Study Short-Form 36 Health Survey (SF-36) was used to assess QoL at baseline and 24 months after ablation.13 The selfadministration mode was strictly followed for QoL surveys. The SF-36 assesses 8 specific QoL domains, namely physical functioning, role limitations due to physical health, bodily pain, general health, vitality, social functioning, role limitations due to emotional problem, and mental health, four each related to physical and mental health, and functioning. For each of the eight subscales, scores were transformed to a scale ranging from 0 to 100, with lower scores representing a lower QoL.
Study endpoint The primary endpoint of this study was long-term freedom from recurrent ATa. Secondary endpoints comprised procedural complications (within 1 month of procedure) including stroke, tamponade/pericardial effusion, phrenic nerve injury, and vascular complications; long-term morbidity (after 1 month of treatment) including death, stroke/transient ischaemic attack (TIA), heart failure, bleeding, sinus nodal dysfunction, and dysthyroidism; and improvement in QoL.
Assuming that SR would be maintained in 75% of patients in the CA group and 50% of patients in the AAD group, a minimum of 85 patients was required in each group at a power of 90% to reach a two-tailed alpha of 0.05. Considering the possibility of dropouts, number of patients was increased by 15% for each group. Statistical analysis was performed using the Statistical Program for Social Sciences (version 20.0 SPSS, Inc., Chicago, IL, USA). Continuous data were expressed as means + standard deviation and analysed with Student’s t-test. x2 test was used for categorical variables. The primary analysis was conducted on an intention-to-treat (ITT) basis, assuming the worst case scenario (failure) when data were missing. Kaplan– Meier survival analysis with the log-rank test was used to compare recurrence-free survival between the two groups. A per-protocol analysis was also performed with patients for whom the primary endpoint was assessed. Secondary analyses were conducted to adjust the primary endpoint for baseline characteristics. The pre-specified covariates were age; sex; duration of AF; left atrial diameter; presence or absence of hypertension, coronary artery disease, valvular heart disease, cardiomyopathy, and chronic obstructive pulmonary disease; and body mass index. All covariates with a P , 0.10 by means of univariate Cox regression were entered into a multivariate Cox regression model. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) are reported. A two-tailed test of significance was used and a P , 0.05 was considered statistically significant.
Results Patient characteristics Two-hundred and one eligible patients were randomized to the CA (n ¼ 101) or AAD (n ¼ 100) groups. In two patients in the CA group, AT terminated spontaneously during mapping and could not be re-induced, and AT converted to SR before ECV in one patient in the AAD group. There were 20 patients who withdrew consent or were lost to follow-up after treatment. Clinical characteristics of the study population are detailed in Table 1.
Clinical outcomes For the 201 enrolled patients, intervention for AT (ablation or ECV) was performed at 10.2 + 6.9 months after index ablation. By ITT analysis, the CA group had a higher success rate, compared with the AAD group (56.4 vs. 34.0%; P ¼ 0.001); this was also the case in per-protocol analysis (178 patients included, 91 vs. 87 in CA vs. AAD; 62.6 vs. 39.1%, respectively; P ¼ 0.002). Adjusted Cox regression analysis showed a significant treatment effect (Wald x2 ¼ 8.5; df ¼ 1; P ¼ 0.004), with an estimated hazard ratio of 0.538 (95% CI: 0.355–0.816) favouring the CA group. In Kaplan–Meier analysis, the CA group showed a higher probability of remaining free from ATa recurrence than the AAD group (log-rank x2 ¼ 8.2; df ¼ 1; P ¼ 0.004) (Figure 2). There was a higher proportion of procedure-related complications in Group CA (7.9% vs. 0; P ¼ 0.012), and of long-term adverse events in Group AAD (10.9 vs. 24.0%; P ¼ 0.014). Hospitalization during the follow-up occurred in 41 (40.6%) patients in Group CA when compared with 62 (62.0%) patients in Group AAD (P ¼ 0.002).
Ablation group Atrial tachycardia ablation was performed in 101 patients with a mean procedural time of 117.9 + 33.8 min. The mean fluoroscopic and radiofrequency time was 16.9 + 3.6 and 61.5 + 13.8 min,
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All the patients from Group AAD underwent ECV at study onset. Patients received OAT with target international normalized ratio (INR) of 2– 3 for at least 1 month before ECV. Antiarrhythmic drugs were prescribed according to guidelines: amiodarone was the first choice for patients with structural cardiomyopathy and class Ic otherwise.12 Doses of each drug were reduced if intolerable adverse reactions occurred, and treatment was stopped if they persisted. After the blanking period, in patients who failed AAD therapy, ECV plus a new kind/combination of AADs was encouraged. Combination of AADs included a class Ic agent with amiodarone, or a calcium-channel blocker.
Statistical analysis
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Table 1
X.D. Zhang et al.
Baseline characteristics
Characteristics
CA (n 5 101)
AAD (n 5 100)
P-value
0.336
................................................................................ 59.9 + 11.4
58.4 + 10.4
71 (70.3)
67 (67.0)
0.614
Total AF duration (months)
68.8 + 50.3
69.8 + 49.5
0.887
Duration of current AF episode (months)
29.1 + 26.0
27.6 + 22.1
0.646
Body mass index (kg/m2) Hypertension
24.1 + 2.5 52 (51.5)
24.0 + 2.3 48 (48.0)
0.818 0.621
Diabetes mellitus
19 (18.8)
20 (20.0)
0.831
Coronary artery disease Valvular heart disease
11 (10.9) 9 (8.9)
13 (13.0) 10 (10.0)
0.645 0.792
Cardiomyopathy
2 (2.0)
3 (3.0)
0.991
Chronic obstructive pulmonary disease
6 (5.9)
8 (8.0)
0.566
Previous stroke or TIA
10 (9.9)
6 (6.0)
0.307
................................................................................
Echocardiographic parameters LAD (mm) 45.8 + 6.3
45.7 + 6.0
0.916
LVEDD (mm)
48.5 + 4.3
49.4 + 4.6
0.128
LVEF
57.9 + 6.5
57.5 + 6.9
0.686
................................................................................ Electrophysiological findings in prior ablation Procedural time (min) 177.9 + 33.8 176.6 + 26.1
0.773
Bidirectional MI block
81 (80.2)
78 (78.0)
0.702
Bidirectional roofline block
86 (85.1)
81 (81.0)
0.433
Electrical cardioversion
91 (90.1)
86 (86.0)
0.370
Previous AADs
69 (68.3)
68 (68.0)
0.962
Values are reported as means + SD or n (%). LAD, left atrial diameter; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; TIA, transient ischaemic attack.
respectively. A total of 122 AT mechanisms in 98 patients were identified (76 patients with one type of AT, 20 with two types and 2 with three types) and AT mechanisms remained unclear in three patients. Atrial tachycardias were terminated by ablation in 94 patients (93.1%), and by ECV in the remaining patients. Pulmonary vein reconnection occurred in 78 patients (77.2%) of Group CA. Details on the electrophysiological findings are given in Table 2. During the follow-up, 44 patients had ATa recurrence, of which 4 were AF recurrence. Among the recurrent patients, 20 received a repeat ablation, 10 of whom (50.0%) maintained SR at the end of follow-up. After the blanking period, 41 patients from the CA group had used a total of 56 AAD. At the last follow-up, 61 patients (60.4%) in Group CA had discontinued AADs permanently with stable SR. There were no ablation-related deaths among enrolled patients. Two patients suffered a stroke during ablation; both had left atrial enlargement (.40 mm), and one had suffered a prior stroke 5 months before ablation. One patient presented with pericardial tamponade that was successfully treated with percutaneous pericardiocentesis. One patient developed right phrenic nerve injury.
Antiarrhythmic drug group Sinus rhythm was restored in only 34 patients of Group AAD (34.0%) with a mean of 1.2 + 0.2 DC biphasic shocks (mean energy delivery of 231 + 62 J). A total of 131 AAD were used in the AAD group, with a mean of 1.3 + 0.5 drugs per patient. Amiodarone was predominantly used in 42 patients, propafenone was administered in 26 patients, and a combination of AAD therapy was used in 31 patients (amiodarone plus propafenone in 19 patients, and propafenone plus verapamil in 12 patients). During the follow-up, 66 patients had ATa recurrence, of which 7 were AF recurrence. Among the recurrent patients, 12 patients received a second ECV plus a new AAD strategy; 2 out of the 12 patients maintained SR at the last follow-up. Twentyfour patients were switched to ablation at 8.6 + 4.2 months; 14 out of the 24 patients were free from recurrent AT/AF. A total of 29 AAD were used in those crossover patients, without ECV before crossover to ablation. Inability to maintain SR, drug intolerance and patient’s choice were the chief reasons for crossover to ablation. A 79-year-old woman and a 71-year-old man died from a cerebrovascular accident 10 and 18 months after treatment, respectively, and a 58-year-old man died from lung cancer 14 months after AAD therapy. During the follow-up, three patients suffered cerebrovascular events, all occurred in ATa with INR ,2. Seven patients had bleeding events; however, they did not require blood transfusion. Three patients developed heart failure. Ten patients (10.0%) discontinued AAD because of side-effects. Owing to sinus nodal dysfunction, four patients underwent pacemaker implantation (two single-chamber and two dual-chamber pacemakers). Four patients developed amiodarone-related dysthyroidism (Table 3).
Predictors of recurrent atrial tachyarrhythmia In univariate Cox analysis, advanced age, female, longer AF duration, and valvular heart disease were associated with recurrence (P , 0.10). Adjusted multivariable Cox regression analysis yielded treatment assignment (HR: 0.538, CI: 0.355 –0.816; P ¼ 0.004), total AF duration (per month, HR: 1.004, CI: 1.000 –1.008; P ¼ 0.036) and advanced age (per year, HR: 1.021, CI: 1.001– 1.042; P ¼ 0.039) as the independent predictors for recurrence in this study.
Quality of life At baseline, no significant difference was found between the two groups. As graphically portrayed in Figure 3, at the 24-month followup, all eight subscales of QoL had improved in the CA group, whereas six of eight subscales were significantly higher in the AAD group.
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Age (years) Male gender
Four patients had vascular complications (one men and three women), including haematoma and pseudoaneurysm, all treated with manual compression and not requiring blood transfusion. No significant PV stenosis was apparent in any patient. With regard to long-term adverse events, a 76-year-old man died from severe heart failure 16 months after ablation, and a 71-year-old woman died from pneumonia 20 months after ablation. Five patients developed heart failure, one patient had a TIA and two patients had minor bleeding events during the follow-up. Owing to the long pause (.2.0 s) after AF ending, one woman underwent implantation of pacemaker (dual chamber pacemaker; Table 3).
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Table 2
Electrophysiological findings
AT mechanisms
Table 3
Study endpoints
n (%)
PV-related ATs
6 (5.9)
Perimitral ATs Roof-dependent ATs
51 (50.5) 30 (29.7)
Left atrial focal ATs
14 (13.9)
CTI-dependent ATs Right atrial focal ATs
17 (16.8) 3 (3.0)
Right atrial incisional ATs
1 (1.0)
................................................................................ PV reconnection, n (%) LSPV LIPV
47 (46.5) 32 (31.7)
RSPV
26 (25.7)
RIPV
25 (24.8)
CA (n 5 101)
AAD (n 5 100)
P-value
Freedom from any AT/AF recurrence
57 (56.4)
34 (34.0)
0.001a
Discontinuation of AADs with stable SR
61 (60.4)
26 (26.0)
,0.001a
Discontinuation of warfarin
70 (69.3)
51 (51.0)
0.008a
................................................................................
Acute complications (,1 month) Stroke 2 (2.0)
0
0.482
Tamponade/pericardial effusion
1 (1.0)
0
1.000
Phrenic nerve injury
1 (1.0)
0
1.000
Vascular complications Total
4 (4.0) 8 (7.9)
0 0
0.132 0.012a
................................................................................ CTI, cavo-tricuspid isthmus; LI, left inferior; LS, left superior; PV, pulmonary vein; RI, right inferior; RS, right superior.
A larger magnitude of improvement was observed for all measures of the SF-36 in the CA group, when compared with the AAD group.
Discussion Efficacy: ablation vs. antiarrhythmic drug Antiarrhythmic drugs remained the cornerstone of AF treatment for decades until CA emerged as the preferred effective approach for
Long-term adverse events (.1 month) Death
2 (2.0)
3 (3.0)
0.991
Stroke/TIA Heart failure
1 (1.0) 5 (5.0)
3 (3.0) 3 (3.0)
0.606 0.729
Bleeding
2 (2.0)
7 (7.0)
0.168
Pacemaker implantation Amiodarone-related dysthyroidism Total
1 (1.0) 0
4 (4.0) 4 (4.0)
0.359 0.127
11 (10.9)
24 (24.0)
0.014a
Values are reported as means + SD or n (%). SR, sinus rhythm; TIA, transient ischaemic attack. a Statistically significant.
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Figure 2 Kaplan– Meier survival curves for freedom from atrial tachyarrhythmia recurrence at 24-month follow-up.
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Figure 3 SF-36 scores at baseline and 24 month. Physical health scales (A) and mental health scales (B) are shown. BP, body pain; GH, general health; MH, mental health; PF, physical functioning; RE, role emotional; RP, role physical; SF, social functioning; VT, vitality.
AF.3 – 7 Wazni et al.3 first demonstrated that CA should be considered as the first-line treatment for symptomatic paroxysmal AF. Moreover, a recent study suggested the superiority of CA to medical therapy in patients with persistent AF; 70.4% of patients in the CA group were free of recurrence, compared with 43.7% in the AAD group (P ¼ 0.002).14 In the era of AF ablation, despite improvements in ablation strategies, a relatively high volume of tissue ablation is performed in AF, especially in persistent AF. Together with remodelling of atria, this provides a favourable substrate for the development of sustained ATs after AF ablation.15 Knecht et al.11 posited that AT
therapy was the final common pathway towards long-term restoration of SR after CA of AF. Because of lack of randomized controlled trials, it had remained unclear whether CA should be the first-line treatment for recurrent ATs. In this randomized controlled trial, we proved that CA is preferred over AAD therapy for patients with recurrent AT after persistent AF ablation. Besides AAD therapy, the PIAF study showed that a rate control strategy was equally effective as a rhythm-control strategy for AF.2 However, a recent clinical trial has proved a significant benefit from ablation, compared with a rate control strategy.16
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In the present study, advanced age and long AF duration were also independent predictors for recurrence. Advancing age has been associated with a more complex LA substrate,17 which may contribute to the higher incidence of recurrence. Recently, a study has found that advanced age was closely related to recurrence after CA in patients with persistent AF.18 With regard to total AF duration, it is believed that long AF duration may result in increased electrical and structural remodelling, thereby affecting the efficacy of therapy.19
Safety: ablation vs. antiarrhythmic drug
Quality of life Several studies have demonstrated that CA improves QoL to a greater extent than AAD therapy in selected patients with AF.4,7,13,20 For the recurrent AT patients, between- and within-group comparisons showed that although both ablation and AAD groups experienced improvements in QoL, Group AAD did not perceive said improvement to the same extent as Group CA. It is believed that restoration and maintenance of SR should improve QoL.23 Moreover, patients randomized to CA experienced fewer long-term adverse events, which may account for the larger beneficial effect of CA on QoL.
Origins of the recurrent atrial tachycardias According to our EP findings, most of the enrolled recurrent ATs can be attributed to the index ablation lesions. All the PV-driven ATs were related to resumption of PV conduction, which has already been proved by Ouyang et al.24 Microre-entrant ATs may be associated with prior extensive electrogram-based ablation. Most macrore-entrant ATs propagated through gaps of recovered conduction of previously complete linear lesions and through initially incomplete lines. Although stepwise ablation strategy is clearly associated with greater procedural success for persistent AF, it is also associated with AT development.15
Cost-effectiveness Economic factors often play a substantial role in guiding treatment selection. Khaykin et al.25 performed an economic evaluation of CA vs. AAD therapy. They demonstrated that medical therapy and CA appeared to be cost neutral after 2 years of follow-up. While CA had a much higher up front cost compared with medical therapy, the higher rate of recurrences and crossover to ablation in the
Limitations Analysis of the primary endpoint was conducted on an ITT basis, a conservative assumption that is not likely to reflect real-life situations. However, the findings held with analysis on a per-protocol basis. It is noteworthy that 24 patients (24.0%) of the AAD group were switched to ablation. Follow-up data were limited by reliance on ECG/Holter and clinical symptoms. However, only three cases were defined as recurrence based solely on reports by patients (two in CA group vs. one in AAD group). Although dropout rate in our study was higher than those in previous studies,3,4 the follow-up period was 12 months in those studies compared with 24 months in this study. Recurrence rates are likely to have been underestimated because of asymptomatic arrhythmia episodes; a recent study found that 12% of patients had asymptomatic recurrences.26 There were five patients from Group CA who were terminated by ECV at the end of ablation. The outcome may be influenced by the concomitant use of AAD in Group CA during the blanking period. Additionally, it is infeasible to identify predictors for complications due to the low incidence of complications. Quality of life was only assessed at baseline and 24-month follow-up.
Conclusions This prospective, randomized controlled study demonstrates superiority of CA over AAD therapy for recurrent AT after persistent AF ablation in terms of SR maintenance, long-term safety and QoL improvement. However, CA use might be limited by a higher risk for periprocedural complications.
Funding This work was supported by a grant from the National Natural Science Foundation of China (30871083) and by a grant from Program of Shanghai Subject Chief Scientist (11XD1404400).
Conflict of interest: none declared.
References 1. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469 –473. 2. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation: Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000;356:1789 –1794. 3. Wazni OM, Marrouche NF, Martin DO, Verma A, Bhargava M, Saliba W, Bash D, Schweikert R, Brachmann J, Gunther J, Gutleben K, Pisano E, Potenza D, Fanelli R, Raviele A, Themistoclakis S, Rossillo A, Bonso A, Natale A. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA 2005;293:2634 –2640. 4. Stabile G, Bertaglia E, Senatore G, De Simone A, Zoppo F, Donnici G, Turco P, Pascotto P, Fazzari M, Vitale DF. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multicenter, randomized, controlled study (Catheter Ablation for the Cure of Atrial Fibrillation Study). Eur Heart J 2006; 27:216–221. 5. Oral H, Pappone C, Chugh A, Good E, Bogun F, Pelosi F Jr, Bates ER, Lehmann MH, Vicedomini G, Augello G, Agricola E, Sala S, Santinelli V, Morady F. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med 2006;354: 934 –941. 6. Pappone C, Augello G, Sala S, Gugliotta F, Vicedomini G, Gulletta S, Paglino G, Mazzone P, Sora N, Greiss I, Santagostino A, LiVolsi L, Pappone N, Radinovic A, Manguso F, Santinelli V. A randomized trial of circumferential pulmonary vein
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The evidence does not suggest that CA is associated with increased procedure-related mortality. In contrast to AAD therapy, CA typically results in only acute and not long-term morbidity, which was commonly observed in other studies.3 – 7,20,21 However, it is infeasible to compare the severity of complications between the two groups. Some study also showed a trend towards an increased risk of stroke/TIA in Group CA compared with Group AAD.3,4,21 The higher risk can be attributed to the influence of catheter manipulation in the left atrium. It is worthy to note that all the patients from Group CA received bridging therapy with heparin. However, continuation of OAT has recently been proved safe for CA of AF, and may even help to reduce periprocedural strokes.22 The overall rate of major procedural complications (including stroke, tamponade/pericardial effusion, phrenic nerve injury, and pulmonary stenosis) was 4.0%, which is consistent with the published literature.4
AAD group led to a rapidly accumulating cost of medical therapy over time.
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assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure. J Am Coll Cardiol 2013;61:1894 –1903. Kistler PM, Sanders P, Fynn SP, Stevenson IH, Spence SJ, Vohra JK, Sparks PB, Kalman JM. Electrophysiologic and electroanatomic changes in the human atrium associated age. J Am Coll Cardiol 2004;44:109 –116. Zhang XD, Gu J, Jiang WF, Zhao L, Wang YL, Liu YG, Zhou L, Gu JN, Wu SH, Xu K, Liu X. The impact of age on the efficacy and safety of catheter ablation for longstanding persistent atrial fibrillation. Int J Cardiol 2013;168:2693 –2698. McCready JW, Smedley T, Lambiase PD, Ahsan SY, Segal OR, Rowland E, Lowe MD, Chow AW. Predictors of recurrence following radiofrequency ablation for persistent atrial fibrillation. Europace 2011;13:355–361. Pappone C, Rosanio S, Augello G, Gallus G, Vicedomini G, Mazzone P, Gulletta S, Gugliotta F, Pappone A, Santinelli V, Tortoriello V, Sala S, Zangrillo A, Crescenzi G, Benussi S, Alfieri O. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003;42:185–197. Blandino A, Toso E, Scaglione M, Anselmino M, Ferraris F, Sardi D, Battaglia A, Gaita F. Long-term efficacy and safety of two different rhythm control strategies in elderly patients with symptomatic persistent atrial fibrillation. J Cardiovasc Electrophysiol 2013;24:731 –738. Page SP, Siddiqui MS, Finlay M, Hunter RJ, Abrams DJ, Dhinoja M, Earley MJ, Sporton SC, Schilling RJ. Catheter ablation for atrial fibrillation on uninterrupted warfarin: can it be done without echo guidance? J Cardiovasc Electrophysiol 2011;22: 265 –270. Singh SN, Tang XC, Singh BN, Dorian P, Reda DJ, Harris CL, Fletcher RD, Sharma SC, Atwood JE, Jacobson AK, Lewis HD Jr, Lopez B, Raisch DW, Ezekowitz MD. SAFE-T Investigators. SAFE-T investigators: quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a veterans affairs cooperative studies program substudy. J Am Coll Cardiol 2006;48:721 – 730. Ouyang F, Antz M, Ernst S, Hachiya H, Mavrakis H, Deger FT, Schaumann A, Chun J, Falk P, Hennig D, Liu X, Ba¨nsch D, Kuck KH. Recovered pulmonary vein conduction as a dominant factor for recurrent atrial tachyarrhythmias after complete circular isolation of the pulmonary veins: lessons from double Lasso technique. Circulation 2005;111:127 –135. Khaykin Y, Wang X, Natale A, Wazni OM, Skanes AC, Humphries KH, Kerr CR, Verma A, Morillo CA. Cost comparison of ablation versus antiarrhythmic drugs as first-line therapy for atrial fibrillation: an economic evaluation of the RAAFT pilot study. J Cardiovasc Electrophysiol 2009;20:7 –12. Verma A, Champagne J, Sapp J, Essebag V, Novak P, Skanes A, Morillo CA, Khaykin Y, Birnie D. Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF): a prospective, multicenter study. JAMA Intern Med 2013;173:149 –156.
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ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study. J Am Coll Cardiol 2006;48:2340 –2347. Jaı¨s P, Cauchemez B, Macle L, Daoud E, Khairy P, Subbiah R, Hocini M, Extramiana F, Sacher F, Bordachar P, Klein G, Weerasooriya R, Cle´menty J, Haı¨ssaguerre M. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation 2008;118:2498 –2505. Gerstenfeld EP, Callans DJ, Dixit S, Russo AM, Nayak H, Lin D, Pulliam W, Siddique S, Marchlinski FE. Mechanisms of organized left atrial tachycardias occurring after pulmonary vein isolation. Circulation 2004;110:1351 –1357. Chugh A, Oral H, Lemola K, Hall B, Cheung P, Good E, Tamirisa K, Han J, Bogun F, Pelosi F Jr, Morady F. Prevalence, mechanisms, and clinical significance of macroreentrant atrial tachycardia during and following left atrial ablation for atrial fibrillation. Heart Rhythm 2005;2:464 – 471. Liu X, Tan HW, Wang XH, Shi HF, Li YZ, Li F, Zhou L, Gu JN. Efficacy of catheter ablation and surgical CryoMaze procedure in patients with long-lasting persistent atrial fibrillation and rheumatic heart disease: a randomized trial. Eur Heart J 2010; 31:2633 –2641. Knecht S, Veenhuyzen G, O’Neill MD, Wright M, Nault I, Weerasooriya R, Miyazaki S, Sacher F, Hocini M, Jaı¨s P, Haı¨ssaguerre M. Atrial tachycardias encountered in the context of catheter ablation for atrial fibrillation part II: mapping and ablation. Pacing Clin Electrophysiol 2009;32:528 –538. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P. 2012 Focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Eur Heart J 2012;33:2719 –2747. Reynolds MR, Walczak J, White SA, Cohen DJ, Wilber DJ. Improvements in symptoms and quality of life in patients with paroxysmal atrial fibrillation treated with radiofrequency catheter ablation versus antiarrhythmic drugs. Circ Cardiovasc Qual Outcomes 2010;3:615 –623. Mont L, Bisbal F, Herna´ndez-Madrid A, Pe´rez-Castellano N, Vin˜olas X, Arenal A, Arribas F, Ferna´ndez-Lozano I, Bodegas A, Cobos A, Matı´a R, Pe´rez-Villacastı´n J, Guerra JM, Avila P, Lo´pez-Gil M, Castro V, Arana JI, Brugada J. on behalf of SARA investigators. Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study). Eur Heart J 2014;35:501 –507. Haı¨ssaguerre M, Sanders P, Hocini M, Takahashi Y, Rotter M, Sacher F, Rostock T, Hsu LF, Bordachar P, Reuter S, Roudaut R, Cle´menty J, Jaı¨s P. Catheter ablation of long-lasting persistent atrial fibrillation: critical structures for termination. J Cardiovasc Electrophysiol 2005;16:1125 –1137. Jones DG, Haldar SK, Hussain W, Sharma R, Francis DP, Rahman-Haley SL, McDonagh TA, Underwood SR, Markides V, Wong T. A randomized trial to
X.D. Zhang et al.
European Heart Journal (2014) 35, 1327–1334 doi:10.1093/eurheartj/ehu017
Arrhythmia/electrophysiology
Optimal rhythm-control strategy for recurrent atrial tachycardia after catheter ablation of persistent atrial fibrillation: a randomized clinical trial Xiao-Dong Zhang, Jun Gu, Wei-Feng Jiang, Liang Zhao, Li Zhou, Yuan-Long Wang, Yu-Gang Liu, and Xu Liu* Received 16 June 2013; revised 17 November 2013; accepted 29 December 2013; online publish-ahead-of-print 3 February 2014
Aim
Although catheter ablation (CA) has replaced antiarrhythmic drugs (AAD) as first-line treatment in selected patients with atrial fibrillation (AF), optimal treatment of recurrent atrial tachycardia (AT) after AF ablation remains unclear. This parallel randomized controlled study compared CA vs. AAD for recurrent AT after persistent AF ablation. ..................................................................................................................................................................................... Methods Two-hundred and one patients (aged 59.1 + 10.9 years, 68.7% male) with recurrent AT after persistent AF ablation were and results enrolled and randomized to either CA (n ¼ 101) or AAD (n ¼ 100) treatment. Primary endpoint was freedom from recurrent atrial tachyarrhythmia (ATa, including AT and AF) at 24-month follow-up. Composite secondary endpoints comprised procedural complications, long-term morbidity and improvement in quality of life (QoL). On an intention-to-treat basis, the CA group had a higher rate of freedom from recurrent ATa (56.4 vs. 34.0%; P ¼ 0.001). Adjusted Cox regression analysis showed a significant treatment effect with a hazard ratio of 0.538 (95% CI: 0.355 –0.816) in favour of CA. There was a higher proportion of periprocedural complications in the CA group (7.9 vs. 0; P ¼ 0.012), and of long-term adverse events in the AAD group (10.9 vs. 24.0%; P ¼ 0.014). Quality of life was significantly higher for CA. ..................................................................................................................................................................................... Conclusions This study demonstrates superiority of CA over AAD for recurrent AT after persistent AF ablation with regard to SR maintenance, long-term safety and QoL improvement. However, CA use might be limited by a higher risk for periprocedural complications.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Atrial fibrillation † Antiarrhythmic drugs † Catheter ablation † Atrial tachycardia † Recurrence † Quality of life
Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia.1 Although mainstay treatment for AF was pharmacological,2 catheter ablation (CA) has emerged as a very promising treatment in the last decade.3 – 6 Many randomized multicentre studies demonstrated the superiority of CA with regard to maintenance of sinus rhythm (SR) and improvement in symptoms, exercise capacity, and quality of life (QoL).3 – 7 However, recurrent atrial tachycardia (AT) after CA of AF is a rapidly growing clinical problem; it undermines the efficacy of CA8,9 because secondary ATs are
often incessant and poorly tolerated by patients. Selecting an appropriate rhythm-control strategy for recurrent AT is paramount to long-term SR maintenance. Catheter ablation and antiarrhythmic drugs (AADs) are the most commonly employed rhythmcontrol strategies. To the best of our knowledge, no study has substantiated preference for re-ablation as the first-line therapy for patients with recurrent AT after ablation. Moreover, the efficacy of treatment for AT and AF is usually not reported separately. We performed a prospective, randomized controlled study to investigate the optimal rhythm-control approach for recurrent AT after CA of persistent AF.
* Corresponding author. Tel: +86 2162821990 2603, Fax: 186 21628 21105, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected]
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Department of Cardiology, Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University, 241 West Huaihai Road, Shanghai 200030, China
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Methods Study population Two-hundred and one patients with recurrent persistent AT out of 986 consecutive patients who had undergone CA of persistent AF at Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University were prospectively enrolled. Inclusion criteria were patients with recurrent persistent AT, who had undergone persistent AF ablation at least 3 months before enrolment, and aged 18 or over. Patients were excluded if they had left atrial thrombus on transoesophageal echocardiography, contraindications to oral anticoagulant therapy (OAT), or any condition with life expectancy ,3 years.
Study design
After the blanking period, any over-30-s episode of atrial tachyarrhythmia (ATa) (including AF and AT) documented electrocardiographically or reported by the patient was considered a recurrence, after which a redo procedure or crossover to the alternative therapy could be performed. Atrial tachyarrhythmia was evaluated at 24 months after treatment. Study design and flow are presented in Figure 1.
Electrophysiological study and ablation procedure All 986 persistent AF patients followed a step-wise ablation strategy, including circumferential pulmonary vein (PV) isolation, complex fractionated atrial electrograms, and linear ablation. The methods and endpoints of ablation were described in detail in our previous study.10 For the enrolled patients, warfarin was discontinued and lowmolecular-weight heparin was used 3 days before ablation. All AADs were discontinued five half-lives before ablation. Unfractionated heparin (80 U/kg) was given after the first trans-septal puncture, and thereafter at 1000 U/h to maintain an activated clotting time between 300 and 350 s. Catheter ablation was performed with the guidance of an electroanatomical mapping system (CARTO, Biosense Webster, CA, USA). Atrial tachycardias could be classified as PV-driven, focal origin, macrore-entry/microre-entry, and unidentified. The approach for AT treatment entailed the following three successive steps: (i) PV origin to the tachycardia is ruled out; (ii) assessment is made for macrore-entrant circuits; and finally, if the mechanism remains undetermined, (iii) conventional mapping for a focal origin (either focal point or
Figure 1 Study design flowchart based on CONSORT guidelines. AAD, antiarrhythmic drug; CA, catheter ablation.
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This was an open, parallel-group, randomized trial. The study complied with the Declaration of Helsinki, and the protocol was approved by the local ethics committee. Eligible patients were assigned to one of the two study arms (CA or AADs) according to the randomization sequence generated by a random number table. All the patients were informed of the investigation and nature of the procedure; informed consents were obtained from all subjects. This study was designed to compare two different rhythm-control strategies in patients with recurrent AT after CA in terms of efficacy, complications and QoL. The first 3 months after procedure [CA/ electrical cardioversion (ECV)] were considered as a ‘blanking period’, during which repeat ablation and ECV should not be used.
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localized re-entry AT) is carried out. Accordingly, ablation strategy for AT included performing PV isolation, linear lesions, or ablating the ‘focus’ as necessary.11 Radio frequency power output was up to 40 W, 43??with 30 –40 s duration for each lesion and saline infusion rate of 20– 25 mL/ min. If the AT was not terminated, 300360 J DC cardioversion was applied to restore SR. After AT termination, patients usually were kept under surveillance for 20 – 30 min, and then PVI and bidirectional block of lines were evaluated and consolidated as required. Re-induction by rapid pacing after termination was at physician’s discretion.
Antiarrhythmic drugs
Blanking period management Antiarrhythmic drug was administered on a routine basis in both arms during the blanking period. As first-choice AAD, amiodarone was given orally at an initial loading dose of 600 mg/day for the first week and 400 mg/day for the following week, and thereafter at a daily maintenance dose of 200 mg/day. Rate control therapy, achieved with the administration of a beta-blocker and a non-dihydropyridine calcium-channel blocker, was used in patients with poorly tolerated AT. Oral anticoagulant therapy was restarted or continued if there was any episode of ATa.
Follow-up Follow-up visits were at 1, 3, 6, 9 months after treatment and every 6 months thereafter. All the participants were scheduled for outpatient clinic, when electrocardiogram (ECG) or 24-h Holter was obtained. Patients were always instructed to obtain an ECG when they had symptoms suggestive of ATa onset. Spiral computed tomography was performed at 3 months after ablation to assess for PV stenosis. Follow-up information was collected from our clinical database and questionnaire administered by telephone.
Quality of life assessment The Medical Outcomes Study Short-Form 36 Health Survey (SF-36) was used to assess QoL at baseline and 24 months after ablation.13 The selfadministration mode was strictly followed for QoL surveys. The SF-36 assesses 8 specific QoL domains, namely physical functioning, role limitations due to physical health, bodily pain, general health, vitality, social functioning, role limitations due to emotional problem, and mental health, four each related to physical and mental health, and functioning. For each of the eight subscales, scores were transformed to a scale ranging from 0 to 100, with lower scores representing a lower QoL.
Study endpoint The primary endpoint of this study was long-term freedom from recurrent ATa. Secondary endpoints comprised procedural complications (within 1 month of procedure) including stroke, tamponade/pericardial effusion, phrenic nerve injury, and vascular complications; long-term morbidity (after 1 month of treatment) including death, stroke/transient ischaemic attack (TIA), heart failure, bleeding, sinus nodal dysfunction, and dysthyroidism; and improvement in QoL.
Assuming that SR would be maintained in 75% of patients in the CA group and 50% of patients in the AAD group, a minimum of 85 patients was required in each group at a power of 90% to reach a two-tailed alpha of 0.05. Considering the possibility of dropouts, number of patients was increased by 15% for each group. Statistical analysis was performed using the Statistical Program for Social Sciences (version 20.0 SPSS, Inc., Chicago, IL, USA). Continuous data were expressed as means + standard deviation and analysed with Student’s t-test. x2 test was used for categorical variables. The primary analysis was conducted on an intention-to-treat (ITT) basis, assuming the worst case scenario (failure) when data were missing. Kaplan– Meier survival analysis with the log-rank test was used to compare recurrence-free survival between the two groups. A per-protocol analysis was also performed with patients for whom the primary endpoint was assessed. Secondary analyses were conducted to adjust the primary endpoint for baseline characteristics. The pre-specified covariates were age; sex; duration of AF; left atrial diameter; presence or absence of hypertension, coronary artery disease, valvular heart disease, cardiomyopathy, and chronic obstructive pulmonary disease; and body mass index. All covariates with a P , 0.10 by means of univariate Cox regression were entered into a multivariate Cox regression model. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) are reported. A two-tailed test of significance was used and a P , 0.05 was considered statistically significant.
Results Patient characteristics Two-hundred and one eligible patients were randomized to the CA (n ¼ 101) or AAD (n ¼ 100) groups. In two patients in the CA group, AT terminated spontaneously during mapping and could not be re-induced, and AT converted to SR before ECV in one patient in the AAD group. There were 20 patients who withdrew consent or were lost to follow-up after treatment. Clinical characteristics of the study population are detailed in Table 1.
Clinical outcomes For the 201 enrolled patients, intervention for AT (ablation or ECV) was performed at 10.2 + 6.9 months after index ablation. By ITT analysis, the CA group had a higher success rate, compared with the AAD group (56.4 vs. 34.0%; P ¼ 0.001); this was also the case in per-protocol analysis (178 patients included, 91 vs. 87 in CA vs. AAD; 62.6 vs. 39.1%, respectively; P ¼ 0.002). Adjusted Cox regression analysis showed a significant treatment effect (Wald x2 ¼ 8.5; df ¼ 1; P ¼ 0.004), with an estimated hazard ratio of 0.538 (95% CI: 0.355–0.816) favouring the CA group. In Kaplan–Meier analysis, the CA group showed a higher probability of remaining free from ATa recurrence than the AAD group (log-rank x2 ¼ 8.2; df ¼ 1; P ¼ 0.004) (Figure 2). There was a higher proportion of procedure-related complications in Group CA (7.9% vs. 0; P ¼ 0.012), and of long-term adverse events in Group AAD (10.9 vs. 24.0%; P ¼ 0.014). Hospitalization during the follow-up occurred in 41 (40.6%) patients in Group CA when compared with 62 (62.0%) patients in Group AAD (P ¼ 0.002).
Ablation group Atrial tachycardia ablation was performed in 101 patients with a mean procedural time of 117.9 + 33.8 min. The mean fluoroscopic and radiofrequency time was 16.9 + 3.6 and 61.5 + 13.8 min,
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All the patients from Group AAD underwent ECV at study onset. Patients received OAT with target international normalized ratio (INR) of 2– 3 for at least 1 month before ECV. Antiarrhythmic drugs were prescribed according to guidelines: amiodarone was the first choice for patients with structural cardiomyopathy and class Ic otherwise.12 Doses of each drug were reduced if intolerable adverse reactions occurred, and treatment was stopped if they persisted. After the blanking period, in patients who failed AAD therapy, ECV plus a new kind/combination of AADs was encouraged. Combination of AADs included a class Ic agent with amiodarone, or a calcium-channel blocker.
Statistical analysis
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Table 1
X.D. Zhang et al.
Baseline characteristics
Characteristics
CA (n 5 101)
AAD (n 5 100)
P-value
0.336
................................................................................ 59.9 + 11.4
58.4 + 10.4
71 (70.3)
67 (67.0)
0.614
Total AF duration (months)
68.8 + 50.3
69.8 + 49.5
0.887
Duration of current AF episode (months)
29.1 + 26.0
27.6 + 22.1
0.646
Body mass index (kg/m2) Hypertension
24.1 + 2.5 52 (51.5)
24.0 + 2.3 48 (48.0)
0.818 0.621
Diabetes mellitus
19 (18.8)
20 (20.0)
0.831
Coronary artery disease Valvular heart disease
11 (10.9) 9 (8.9)
13 (13.0) 10 (10.0)
0.645 0.792
Cardiomyopathy
2 (2.0)
3 (3.0)
0.991
Chronic obstructive pulmonary disease
6 (5.9)
8 (8.0)
0.566
Previous stroke or TIA
10 (9.9)
6 (6.0)
0.307
................................................................................
Echocardiographic parameters LAD (mm) 45.8 + 6.3
45.7 + 6.0
0.916
LVEDD (mm)
48.5 + 4.3
49.4 + 4.6
0.128
LVEF
57.9 + 6.5
57.5 + 6.9
0.686
................................................................................ Electrophysiological findings in prior ablation Procedural time (min) 177.9 + 33.8 176.6 + 26.1
0.773
Bidirectional MI block
81 (80.2)
78 (78.0)
0.702
Bidirectional roofline block
86 (85.1)
81 (81.0)
0.433
Electrical cardioversion
91 (90.1)
86 (86.0)
0.370
Previous AADs
69 (68.3)
68 (68.0)
0.962
Values are reported as means + SD or n (%). LAD, left atrial diameter; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; TIA, transient ischaemic attack.
respectively. A total of 122 AT mechanisms in 98 patients were identified (76 patients with one type of AT, 20 with two types and 2 with three types) and AT mechanisms remained unclear in three patients. Atrial tachycardias were terminated by ablation in 94 patients (93.1%), and by ECV in the remaining patients. Pulmonary vein reconnection occurred in 78 patients (77.2%) of Group CA. Details on the electrophysiological findings are given in Table 2. During the follow-up, 44 patients had ATa recurrence, of which 4 were AF recurrence. Among the recurrent patients, 20 received a repeat ablation, 10 of whom (50.0%) maintained SR at the end of follow-up. After the blanking period, 41 patients from the CA group had used a total of 56 AAD. At the last follow-up, 61 patients (60.4%) in Group CA had discontinued AADs permanently with stable SR. There were no ablation-related deaths among enrolled patients. Two patients suffered a stroke during ablation; both had left atrial enlargement (.40 mm), and one had suffered a prior stroke 5 months before ablation. One patient presented with pericardial tamponade that was successfully treated with percutaneous pericardiocentesis. One patient developed right phrenic nerve injury.
Antiarrhythmic drug group Sinus rhythm was restored in only 34 patients of Group AAD (34.0%) with a mean of 1.2 + 0.2 DC biphasic shocks (mean energy delivery of 231 + 62 J). A total of 131 AAD were used in the AAD group, with a mean of 1.3 + 0.5 drugs per patient. Amiodarone was predominantly used in 42 patients, propafenone was administered in 26 patients, and a combination of AAD therapy was used in 31 patients (amiodarone plus propafenone in 19 patients, and propafenone plus verapamil in 12 patients). During the follow-up, 66 patients had ATa recurrence, of which 7 were AF recurrence. Among the recurrent patients, 12 patients received a second ECV plus a new AAD strategy; 2 out of the 12 patients maintained SR at the last follow-up. Twentyfour patients were switched to ablation at 8.6 + 4.2 months; 14 out of the 24 patients were free from recurrent AT/AF. A total of 29 AAD were used in those crossover patients, without ECV before crossover to ablation. Inability to maintain SR, drug intolerance and patient’s choice were the chief reasons for crossover to ablation. A 79-year-old woman and a 71-year-old man died from a cerebrovascular accident 10 and 18 months after treatment, respectively, and a 58-year-old man died from lung cancer 14 months after AAD therapy. During the follow-up, three patients suffered cerebrovascular events, all occurred in ATa with INR ,2. Seven patients had bleeding events; however, they did not require blood transfusion. Three patients developed heart failure. Ten patients (10.0%) discontinued AAD because of side-effects. Owing to sinus nodal dysfunction, four patients underwent pacemaker implantation (two single-chamber and two dual-chamber pacemakers). Four patients developed amiodarone-related dysthyroidism (Table 3).
Predictors of recurrent atrial tachyarrhythmia In univariate Cox analysis, advanced age, female, longer AF duration, and valvular heart disease were associated with recurrence (P , 0.10). Adjusted multivariable Cox regression analysis yielded treatment assignment (HR: 0.538, CI: 0.355 –0.816; P ¼ 0.004), total AF duration (per month, HR: 1.004, CI: 1.000 –1.008; P ¼ 0.036) and advanced age (per year, HR: 1.021, CI: 1.001– 1.042; P ¼ 0.039) as the independent predictors for recurrence in this study.
Quality of life At baseline, no significant difference was found between the two groups. As graphically portrayed in Figure 3, at the 24-month followup, all eight subscales of QoL had improved in the CA group, whereas six of eight subscales were significantly higher in the AAD group.
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Age (years) Male gender
Four patients had vascular complications (one men and three women), including haematoma and pseudoaneurysm, all treated with manual compression and not requiring blood transfusion. No significant PV stenosis was apparent in any patient. With regard to long-term adverse events, a 76-year-old man died from severe heart failure 16 months after ablation, and a 71-year-old woman died from pneumonia 20 months after ablation. Five patients developed heart failure, one patient had a TIA and two patients had minor bleeding events during the follow-up. Owing to the long pause (.2.0 s) after AF ending, one woman underwent implantation of pacemaker (dual chamber pacemaker; Table 3).
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Optimal rhythm-control strategy for recurrent atrial tachycardia
Table 2
Electrophysiological findings
AT mechanisms
Table 3
Study endpoints
n (%)
PV-related ATs
6 (5.9)
Perimitral ATs Roof-dependent ATs
51 (50.5) 30 (29.7)
Left atrial focal ATs
14 (13.9)
CTI-dependent ATs Right atrial focal ATs
17 (16.8) 3 (3.0)
Right atrial incisional ATs
1 (1.0)
................................................................................ PV reconnection, n (%) LSPV LIPV
47 (46.5) 32 (31.7)
RSPV
26 (25.7)
RIPV
25 (24.8)
CA (n 5 101)
AAD (n 5 100)
P-value
Freedom from any AT/AF recurrence
57 (56.4)
34 (34.0)
0.001a
Discontinuation of AADs with stable SR
61 (60.4)
26 (26.0)
,0.001a
Discontinuation of warfarin
70 (69.3)
51 (51.0)
0.008a
................................................................................
Acute complications (,1 month) Stroke 2 (2.0)
0
0.482
Tamponade/pericardial effusion
1 (1.0)
0
1.000
Phrenic nerve injury
1 (1.0)
0
1.000
Vascular complications Total
4 (4.0) 8 (7.9)
0 0
0.132 0.012a
................................................................................ CTI, cavo-tricuspid isthmus; LI, left inferior; LS, left superior; PV, pulmonary vein; RI, right inferior; RS, right superior.
A larger magnitude of improvement was observed for all measures of the SF-36 in the CA group, when compared with the AAD group.
Discussion Efficacy: ablation vs. antiarrhythmic drug Antiarrhythmic drugs remained the cornerstone of AF treatment for decades until CA emerged as the preferred effective approach for
Long-term adverse events (.1 month) Death
2 (2.0)
3 (3.0)
0.991
Stroke/TIA Heart failure
1 (1.0) 5 (5.0)
3 (3.0) 3 (3.0)
0.606 0.729
Bleeding
2 (2.0)
7 (7.0)
0.168
Pacemaker implantation Amiodarone-related dysthyroidism Total
1 (1.0) 0
4 (4.0) 4 (4.0)
0.359 0.127
11 (10.9)
24 (24.0)
0.014a
Values are reported as means + SD or n (%). SR, sinus rhythm; TIA, transient ischaemic attack. a Statistically significant.
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Figure 2 Kaplan– Meier survival curves for freedom from atrial tachyarrhythmia recurrence at 24-month follow-up.
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Figure 3 SF-36 scores at baseline and 24 month. Physical health scales (A) and mental health scales (B) are shown. BP, body pain; GH, general health; MH, mental health; PF, physical functioning; RE, role emotional; RP, role physical; SF, social functioning; VT, vitality.
AF.3 – 7 Wazni et al.3 first demonstrated that CA should be considered as the first-line treatment for symptomatic paroxysmal AF. Moreover, a recent study suggested the superiority of CA to medical therapy in patients with persistent AF; 70.4% of patients in the CA group were free of recurrence, compared with 43.7% in the AAD group (P ¼ 0.002).14 In the era of AF ablation, despite improvements in ablation strategies, a relatively high volume of tissue ablation is performed in AF, especially in persistent AF. Together with remodelling of atria, this provides a favourable substrate for the development of sustained ATs after AF ablation.15 Knecht et al.11 posited that AT
therapy was the final common pathway towards long-term restoration of SR after CA of AF. Because of lack of randomized controlled trials, it had remained unclear whether CA should be the first-line treatment for recurrent ATs. In this randomized controlled trial, we proved that CA is preferred over AAD therapy for patients with recurrent AT after persistent AF ablation. Besides AAD therapy, the PIAF study showed that a rate control strategy was equally effective as a rhythm-control strategy for AF.2 However, a recent clinical trial has proved a significant benefit from ablation, compared with a rate control strategy.16
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Optimal rhythm-control strategy for recurrent atrial tachycardia
In the present study, advanced age and long AF duration were also independent predictors for recurrence. Advancing age has been associated with a more complex LA substrate,17 which may contribute to the higher incidence of recurrence. Recently, a study has found that advanced age was closely related to recurrence after CA in patients with persistent AF.18 With regard to total AF duration, it is believed that long AF duration may result in increased electrical and structural remodelling, thereby affecting the efficacy of therapy.19
Safety: ablation vs. antiarrhythmic drug
Quality of life Several studies have demonstrated that CA improves QoL to a greater extent than AAD therapy in selected patients with AF.4,7,13,20 For the recurrent AT patients, between- and within-group comparisons showed that although both ablation and AAD groups experienced improvements in QoL, Group AAD did not perceive said improvement to the same extent as Group CA. It is believed that restoration and maintenance of SR should improve QoL.23 Moreover, patients randomized to CA experienced fewer long-term adverse events, which may account for the larger beneficial effect of CA on QoL.
Origins of the recurrent atrial tachycardias According to our EP findings, most of the enrolled recurrent ATs can be attributed to the index ablation lesions. All the PV-driven ATs were related to resumption of PV conduction, which has already been proved by Ouyang et al.24 Microre-entrant ATs may be associated with prior extensive electrogram-based ablation. Most macrore-entrant ATs propagated through gaps of recovered conduction of previously complete linear lesions and through initially incomplete lines. Although stepwise ablation strategy is clearly associated with greater procedural success for persistent AF, it is also associated with AT development.15
Cost-effectiveness Economic factors often play a substantial role in guiding treatment selection. Khaykin et al.25 performed an economic evaluation of CA vs. AAD therapy. They demonstrated that medical therapy and CA appeared to be cost neutral after 2 years of follow-up. While CA had a much higher up front cost compared with medical therapy, the higher rate of recurrences and crossover to ablation in the
Limitations Analysis of the primary endpoint was conducted on an ITT basis, a conservative assumption that is not likely to reflect real-life situations. However, the findings held with analysis on a per-protocol basis. It is noteworthy that 24 patients (24.0%) of the AAD group were switched to ablation. Follow-up data were limited by reliance on ECG/Holter and clinical symptoms. However, only three cases were defined as recurrence based solely on reports by patients (two in CA group vs. one in AAD group). Although dropout rate in our study was higher than those in previous studies,3,4 the follow-up period was 12 months in those studies compared with 24 months in this study. Recurrence rates are likely to have been underestimated because of asymptomatic arrhythmia episodes; a recent study found that 12% of patients had asymptomatic recurrences.26 There were five patients from Group CA who were terminated by ECV at the end of ablation. The outcome may be influenced by the concomitant use of AAD in Group CA during the blanking period. Additionally, it is infeasible to identify predictors for complications due to the low incidence of complications. Quality of life was only assessed at baseline and 24-month follow-up.
Conclusions This prospective, randomized controlled study demonstrates superiority of CA over AAD therapy for recurrent AT after persistent AF ablation in terms of SR maintenance, long-term safety and QoL improvement. However, CA use might be limited by a higher risk for periprocedural complications.
Funding This work was supported by a grant from the National Natural Science Foundation of China (30871083) and by a grant from Program of Shanghai Subject Chief Scientist (11XD1404400).
Conflict of interest: none declared.
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